Download Histone Deacetylase Inhibitors in Cancer Therapy

VOLUME 27 䡠 NUMBER 32 䡠 NOVEMBER 10 2009
JOURNAL OF CLINICAL ONCOLOGY
R E V I E W
A R T I C L E
Histone Deacetylase Inhibitors in Cancer Therapy
Andrew A. Lane and Bruce A. Chabner
See accompanying article on page 5410
From the Massachusetts General
Hospital Cancer Center, Boston, MA.
Submitted January 27, 2009; accepted
March 27, 2009; published online
ahead of print at www.jco.org on
October 13, 2009.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Corresponding author: Bruce A.
Chabner, MD, Massachusetts General
Hospital Cancer Center, 55 Fruit St,
Boston, MA 02214; email: bchabner@
partners.org.
© 2009 by American Society of Clinical
Oncology
0732-183X/09/2732-5459/$20.00
DOI: 10.1200/JCO.2009.22.1291
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Purpose
Epigenetic processes are implicated in cancer causation and progression. The acetylation status of
histones regulates access of transcription factors to DNA and influences levels of gene
expression. Histone deacetylase (HDAC) activity diminishes acetylation of histones, causing
compaction of the DNA/histone complex. This compaction blocks gene transcription and inhibits
differentiation, providing a rationale for developing HDAC inhibitors.
Methods
In this review, we explore the biology of the HDAC enzymes, summarize the pharmacologic properties
of HDAC inhibitors, and examine results of selected clinical trials. We consider the potential of these
inhibitors in combination therapy with targeted drugs and with cytotoxic chemotherapy.
Results
HDAC inhibitors promote growth arrest, differentiation, and apoptosis of tumor cells, with minimal
effects on normal tissue. In addition to decompaction of the histone/DNA complex, HDAC
inhibition also affects acetylation status and function of nonhistone proteins. HDAC inhibitors have
demonstrated antitumor activity in clinical trials, and one drug of this class, vorinostat, is US Food
and Drug Administration approved for the treatment of cutaneous T-cell lymphoma. Other inhibitors in
advanced stages of clinical development, including depsipeptide and MGCD0103, differ from vorinostat in structure and isoenzyme specificity, and have shown activity against lymphoma, leukemia, and
solid tumors. Promising preclinical activity in combination with cytotoxics, inhibitors of heat shock
protein 90, and inhibitors of proteasome function have led to combination therapy trials.
Conclusion
HDAC inhibitors are an important emerging therapy with single-agent activity against multiple
cancers, and have significant potential in combination use.
J Clin Oncol 27:5459-5468. © 2009 by American Society of Clinical Oncology
INTRODUCTION
Epigenetic modulation of gene expression is as an
important regulatory process in cell biology.1 Gene
regulation occurs in the context of packaging of
DNA into an organizing structure, the nucleosome,
composed of a DNA strand wound around a core of
eight histone proteins.2 The N-terminal tails of each
histone extend outward through the DNA strand.
Amino acid residues on the histone tail are modified by post-translational acetylation, methylation, and phosphorylation.3 These modifications
change the secondary structure of the histone protein tails in relation to the DNA strands, increase the
distance between DNA and histones, and increase
accessibility of transcription factors to gene promoter regions.4 Deacetylation, demethylation, and
dephosphorylation of histones have the opposite effect of decreasing access of transcription factors to
promoter regions. Developmental and regulatory
processes within the cell are strongly influenced by
histone modification. Emerging data now implicate
histone modification in the pathobiology of cancer
and other diseases. Histone acetylation is mediated
by histone acetyl transferases,5 while acetyl groups
are removed by histone deacetylases (HDACs).6
This review will focus on the current role and potential of HDAC inhibitors in cancer treatment. Histone methylation7 and phosphorylation,8 also the
subjects of therapeutic research, are less well understood processes, and will not be considered in
this discussion.
The HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid) is approved for treating refractory cutaneous T-cell lymphoma (CTCL).9
Other HDAC inhibitors have entered clinical trials
in both solid tumors and hematologic malignancies. Herein we summarize the biology of HDAC
proteins and their postulated role in cancer pathogenesis. We describe the HDAC inhibitors under
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Lane and Chabner
ings. In many tumor cell lines, inhibition or down-regulation of
HDACs causes the upregulation of the cell cycle gene p21WAF1/CIP1,
blocking the Cyclin D/CDK4 complex, and leading to cell cycle arrest
and differentiation.35,36
HDACs also have a critical role in modulating the balance between pro- and antiapoptotic proteins.37 HDAC inhibition upregulates the intrinsic apoptosis pathway through induction of the
proapoptotic genes Bmf38 and Bim.39 Apoptosis induced by HDAC
inhibitors can be blocked by overexpression of antiapoptotic Bcl-2.40
Further, hyperacetylation stabilizes the p53 protein, promoting both
cell cycle arrest and expression of proapoptotic genes.41 HDAC inhibition also induces elements of the extrinsic apoptotic pathway by
increasing the expression of death receptor proteins, including Fas,
TNF-␣, and the TRAIL receptor.42,43
HDAC inhibition may also affect tumor cell survival by blocking tumor angiogenesis, and by inhibiting intracellular stress response pathways. HDAC inhibitors increase acetylation of the
pro-angiogenic transcription factor HIF-1␣, enhancing its degradation.25 In addition, HDAC inhibitors decrease expression of the vascular endothelial growth factor receptor.44 HDAC inhibition also
increases generation of intracellular reactive oxygen species, and impairs handling of misfolded proteins by influencing endoplasmic reticulum stress responses.45,46 By inducing hyperacetylation of HSP90,
HDAC inhibitors disrupt the function of this critical protein chaperone that normally protects cellular and cancer-related proteins from
degradation (Fig 1).29 Affected oncogenic proteins include BCRABL, epidermal growth factor receptor, human epidermal growth
factor receptor 2/neu, FLT3, Akt, and c-Raf.17,47 The important effects of
HDAC inhibition on HSP90 function have stimulated interest in clinical trials of the combination of HDAC and HSP90 inhibitors.
As summarized earlier, modulation of histone and, more generally, protein acetylation, alters pathways that promote proliferation,
angiogenesis, and survival in cancer cells. Moreover, HDAC inhibitors
have global effects on gene expression, and may affect as yet unrealized
cellular processes.48-50 Successful therapeutic use of HDAC inhibitors
may thus depend on subtleties of the cellular milieu, the specific
HDACs targeted, and the relative dependence of the malignant phenotype on the unique set of pathways influenced by a specific drug.
clinical investigation, their pharmacologic properties, their approved
indications, and their potential as single agents and in combination therapy.
BIOLOGY OF HDACs
In the 1970s, the Friend erythroleukemia cell line was found to differentiate in the presence of dimethyl sulfoxide or butyrate.10,11 Many
compounds with the ability to promote differentiation of tumor cell
lines, particularly those with a planar-polar configuration, induced
accumulation of hyperacetylated histones.12 Histone hypoacetylation
was also found to be associated with gene silencing, as in the inactivated female X chromosome.13 Seminal experiments showed that
treatment of cells with the short-chain fatty acid sodium butyrate
caused hyperacetylation of histone octamers. This histone modification increased the spatial separation of DNA from histone and enhanced binding of transcription factor complexes to DNA.14 Later,
the first mammalian HDACs were cloned on the basis of their
binding to known small molecule inhibitors of histone deacetylation.15 These genes were homologous to yeast transcriptional repressors, strengthening the evidence that histone deacetylation suppresses
gene expression.
Further work has identified at least 18 human HDACs, with
varying function, localization, and substrates (Table 1).16,17 The four
classes of HDACs are grouped by their homology to yeast proteins.
Classes I, II, and IV all contain a zinc (Zn) molecule in their active site
and are inhibited by the pan-HDAC inhibitors. The seven different
class III HDACs (sirtuins), are homologous to the yeast Sir2, do not
contain Zn in the active site, and are not inhibited by any current
HDAC inihibitors.18
The function of many nonhistone proteins is also controlled
by acetylation on lysine residues, and, in fact, HDACs may have
appeared evolutionarily before histone-like genes.19,20 HDACmediated deacetylation alters the transcriptional activity of nuclear
transcription factors, including p53,21 E2F,22 c-Myc,23 nuclear factor ␬B
(NF-␬B),24 hypoxia-inducible factor 1␣ (HIF-1␣),25as well as estrogen
receptor ␣26 and the androgen receptor complexes.27 Other cancerrelated proteins are acetylated, including the DNA repair enzyme
Ku70,28 the chaperone heat shock protein 90 (HSP90),29 the signaling pathway intermediate STAT3,30 and alpha-tubulin.31
Knockout mouse models have demonstrated the importance of
HDACs in cell differentiation. Genetic deletion of the class I genes
HDAC132 or HDAC233 results in embryonic or perinatal lethality,
respectively. Class II HDAC knockout mice are viable and fertile
(with the exception of HDAC7 knockouts), but all display developmental abnormalities.34 HDAC inhibitors recapitulate these find-
HDACs IN CANCER
A common finding in cancer cells is high level expression of HDAC
isoenzymes and a corresponding hypoacetylation of histones.51,52 A
study of normal and malignant tissues revealed a consistent pattern:
higher levels of histone acetylation in normal lymphoid tissue as compared to lymphomas, and in normal colonic epithelium as compared
Table 1. HDACs
Class
Enzymes
Zn2⫹ Dependent
Localization
Expression
I
IIa
IIb
III
IV
HDAC1, HDAC2, HDAC3, HDAC8
HDAC4, HDAC5, HDAC7, HDAC9
HDAC6, HDAC10
Sirtuins 1-7
HDAC11
Yes
Yes
Yes
No
Yes
Nucleus
Nucleus and cytoplasm
Cytoplasm
Variable
Nucleus and cytoplasm
Ubiquitous
Tissue specific
Tissue specific
Variable
Ubiquitous
Abbreviation: HDAC, histone deacetylase; Zn, zinc.
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Histone Deacetylase Inhibitors in Cancer Therapy
HDAC6
Ac
HDAC6
HSP90
HDAC
inhibitor
HSP90
cancer
protein X
of many tumor types, including breast cancer.61 However, in a study of
invasive breast cancer, increased HDAC1 and 3 expression was paradoxically correlated with improved disease-free survival.62 In patients
with non–small-cell lung cancer (NSCLC), lower expression of class II
HDACs was associated with a poor prognosis.63 These contradictions
underscore the caveats of predicting the effects of inhibiting a cellular
pathway controlled by multiple isoenzymes which have complex
tissue-specific and tumor-specific expression patterns.
cancer
protein X
degradation
Fig 1. The interaction between heat shock protein 90 (HSP90) and histone
deacetylase 6 (HDAC6). HSP90 chaperones several oncogenes (cancer protein
X). HSP90 function is inhibited by acetylation on lysine residues. When cells are
treated with an HDAC inhibitor, HDAC6 activity is blocked, HSP90 becomes
hyperacetylated (Ac), and client cancer proteins are degraded by the proteasome.
to colon adenocarcinomas.53 HDAC1 enzyme expression is higher in
colon adenocarcinoma cells than in normal colon epithelium.54 Loss
of genetic gatekeeper function in precancerous lesions may be associated with increased activity of HDACs. HDAC2 expression is elevated
in colon cancer cells, possibly as a result of adenomatosis polyposis coli
(APC) gene deficiency, an early event in colon carcinogenesis. Knockdown of HDAC2 expression by short inhibitory RNAs or treatment
with an HDAC inhibitor–induced growth arrest of a colon cancer cell
line, and HDAC inhibitor-treated APC mutant mice developed fewer
colon adenomas than untreated animals.55
Increased HDAC activity, and the resultant transcriptional repression of genes essential to hematopoietic differentiation, may
play a critical role in the pathogenesis of certain leukemias. The
PML-RAR␣ protein product of the t(15;17) translocation in acute
promyelocytic leukemia, as well as the core binding factor leukemia
gene products AML1-ETO and CBF␤-MYH11 act as transcriptional
repressors through their recruitment of HDACs to gene promoter
regions. All-trans-retinoic acid, an effective therapy for acute promyelocytic leukemia, blocks the recruitment of HDACs to the
transcriptional regulatory complex with RAR␣ and causes tumor
cell differentiation.56,57
Given the vast biologic effects of HDAC inhibition, one might
expect HDAC inhibitors to have a narrow therapeutic window. However, data suggest that transformed cells are more sensitive to HDAC
inhibitor-induced apoptosis than are normal cells. CTCL cells undergo higher rates of apoptosis than normal lymphocytes in response
to HDAC inhibitor treatment.58 Similarly, transformed human fibroblasts have a decreased growth rate and lower viability than normal
fibroblasts when these cell types are grown in the presence of HDAC
inhibitors.59 These differences in sensitivity may be due to addiction of
tumor cells to certain cellular pathways, concomitant genetic defects,
or an inability of transformed cells to upregulate rescue pathways after
a toxic insult.60
Unexpected, and perhaps contradictory, results reinforce the
complexity of the cellular pathways influenced by HDACs. In vitro
and in vivo, HDAC inhibitors cause cell cycle arrest and differentiation
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HDAC INHIBITORS
HDAC inhibitors have attracted interest because of their ability to
induce differentiation of malignant cells in culture.64 The first of these
was hexamethylene bisacetamide, and its more potent analogs of the
so-called hybrid polar class. A related fungal product, trichostatin A,
displayed similar differentiating effects in vitro. The activity of these
compounds, all derivatives of hydroxamic acid, prompted the synthesis of vorinostat (suberoylanilide hydroxamic acid; Fig 2).64,65
To date, more than 15 HDAC inhibitors have been tested in
preclinical and early clinical studies. The common mechanism of
action of these drugs is to bind a critical Zn2⫹ ion required for catalytic
function of the HDAC enzyme.66 The detailed chemistry and development of these drugs have been reviewed.17,67 The important clinical
implication is that although these compounds were selected for their
ability to inhibit histone deacetylation, they have widely varying potency and HDAC isoenzyme specificity, and variable effects on acetylation of nonhistone substrates (Table 2).68 The various inhibitors
HMBA
Vorinostat
Depsipeptide
MGCD0103
Fig 2. Chemical structure of selected histone deacetylase inhibitors. HMBA,
hexamethylene bisacetamide.
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Lane and Chabner
Table 2. Selected HDAC Inhibitors in Clinical Use or Development
Compound by Class
Hydroxamic acid
Vorinostat (Zolinza), suberoylanilide hydroxamic
acid (SAHA)
Trichostatin A (TSA)
LAQ824
Panobinostat (LBH589)
Belinostat (PXD101)
ITF2357
Cyclic tetrapeptide
Depsipeptide (romidepsin, FK228)
Benzamide
Entinostat (SNDX-275/MS-275)
MGCD0103
Short-chain aliphatic acids
Valproic acid
Phenyl butyrate
AN-9, pivanex
Manufacturer
In Vitro Potencyⴱ
HDAC Class Specificity
Merck, Whitehouse Station, NJ
Novartis, Basel, Switzerland
Novartis
CuraGen, Branford, CT
Italfarmaco SpA, Cinisello Balsamo, Italy
Gloucester Pharmaceuticals, Cambridge, MA
I (particularly HDAC1, HDAC2)
nM
Syndax Pharmaceuticals, Waltham, MA
Celgene, Summit, NJ; MethylGene, Montreal,
Quebec
I (particularly HDAC1, HDAC2, HDAC3)
I
␮M
nM
I, IIa
I, IIa
NA
mM
mM
␮M
Titan Pharmaceutical, San Francisco, CA
II,
II,
II,
II,
II,
II,
␮M
␮M
nM
nM
␮M
␮M
I,
I,
I,
I,
I,
I,
IV
IV
IV
IV
IV
IV
Abbreviations: HDAC, histone deacetylase; NA, not available.
ⴱ
Reported range of drug concentration necessary for in vitro inhibition of histone deacetylation in cell lines.
have nonoverlapping effects on transformed cells in vitro and would
thus be expected to have differing efficacies, toxicities, and therapeutic
uses in patients.
HDAC INHIBITOR PHARMACOLOGY
The only US Food and Drug Administration–approved HDAC inhibitor is vorinostat (Zolinza; Merck, Whitehouse Station, NJ).64 The
chemical class, HDAC isoenzyme specificity, and potency of vorinostat and selected inhibitors in clinical development, are listed in Table
2.17,67 HDAC inhibitors have a relatively short half-life in plasma (t1/2
approximately 2 hours for vorinostat,69,70 8 hours for depsipeptide,71
9 hours for MGCD010372), and undergo hepatic metabolism. For
depsipeptide, the principle enzyme responsible for metabolism is
CYP3A4. The majority of the drug and its metabolites are eliminated
via biliary and fecal routes; small amounts of parent and metabolites
are detectable in the urine.73 Similar pharmacokinetics are observed
for vorinostat, which is metabolized principally via glucuronidation.70
Interestingly, the HDAC inhibitors show pharmacodynamic effects
well beyond the time of drug metabolism. For example, despite the
short half-life of vorinostat in the blood, accumulation of acetylated
histones in peripheral-blood cells continues up to 10 hours after an
oral dose.69
RATIONALE FOR COMBINATION THERAPY
Multiple preclinical studies and clinical data support the use of HDAC
inhibitors in combination with other cancer therapies.67 Since HDAC
inhibitors alter the balance in favor of proapoptotic pathways, they
have been tested with conventional chemotherapeutic agents including platinums, taxanes, gemcitabine, fluorouracil, and epirubicin in
solid tumors.74 In addition, many of the earliest investigations of
HDAC inhibitors were conducted in patients with myelodysplastic
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syndrome (MDS) and myeloid leukemia. These disorders exhibit abnormal recruitment of HDACs to nuclear protein complexes and have
common recurring histone modifications.75 These observations have
formed the basis for combining HDAC inhibitors with the DNA
methyltransferase inhibitor 5-azacytidine in MDS/acute myeloid leukemia (AML), or the differentiating agent all-trans-retinoic acid, in
acute promyelocytic leukemia.76,77 Finally, HDAC inhibitors enhance
tumor cell radiosensitivity and are being tested with ionizing radiation
in solid tumors.78
An important emerging target for HDAC inhibitors lies in the
cellular mechanisms for handling misfolded proteins, which are degraded by the proteasome. Disruption of the proteasome system with
bortezomib increases endoplasmic reticulum stress and apoptosis in
multiple myeloma cells.79 However, an alternative pathway, the aggresome, also participates in the disposal of ubiquitinated misfolded proteins.80 This pathway is upregulated in the setting of
proteasome inhibition and is dependent on the cytoplasmically localized HDAC6.81 Inhibition of HDAC6 via short hairpin RNA, by the
HDAC6-specific inhibitor tubacin, or by the pan-HDAC inhibitors
vorinostat or LBH589, all resulted in synergistic apoptosis when combined with bortezomib.82,83 These effects are also observed in nonmyeloma cell lines, suggesting a more generalizable target.84 In addition
to the proteasome and the aggresome, the cytoplasmic HSP system is
also influenced by HDAC6, through deacetylation of lysines on
HSP90 (Fig 1).85 HDAC inhibition results in loss of HSP90 chaperone
function and enhanced degradation of BCR-ABL, human epidermal
growth factor receptor 2/neu, and FLT3; these data suggest potential
synergy of HDAC inhibitors with imatinib, traztuzumab, or FLT3 inhibitors in cancers driven by amplified or mutated tyrosine kinases.47
HDAC INHIBITOR RESISTANCE
HDAC inhibitor resistance has been examined in vitro to further our
understanding of HDAC biology, and to suggest strategies for rational
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Histone Deacetylase Inhibitors in Cancer Therapy
combination therapy. A mutation in HDAC2 was found in cell lines
resistant to trichostatin A, and the same mutation was found in a
subset of primary human tumor samples.86 Other proposed mechanisms of HDAC inhibitor resistance include upregulation of cellular
antioxidant pathways, increased expression of the antiapoptotic protein Bcl-2 and the stress-responsive transcription factor NF-␬B, and
use of alternative gene silencing pathways such as DNA methylation.87
Finally, the unfolded protein response pathway is implicated in
HDAC inhibitor resistance. An AML cell line resistant to growth
inhibition induced by treatment with the hydroxamate class of drugs
demonstrated hyperacetylation of HSP90 at baseline, but was then
sensitive to treatment with 17-AAG, a geldanamycin derivative and
HSP90 inhibitor.88 17-AAG synergizes with tubacin, an inhibitor of
HDAC6, or with short interfering RNA against HDAC6, in killing
primary leukemia cells.89 Strategies to avoid resistance to HDAC inhibitors may employ combination therapies simultaneously targeting
both HDACs and DNA methylation, or HDACs and HSP90.
CLINICAL TRIALS
A summary of selected HDAC inhibitor trials is shown in Table 3.90-101
Due to space limitations, we discuss data on three agents of different
classes with evidence of anticancer activity in phase II trials.
VORINOSTAT IN CTCL
Dose finding phase I trials of vorinostat were performed with both
intravenous and oral formulations, in patients with advanced solid
tumors and hematologic malignancies.69,102 The maximum tolerated
dose (MTD) of the oral formulation was 400 mg/d for continuous
dosing. Dose-limiting toxicities (DLTs) were myelosuppression, fatigue, diarrhea, anorexia, and dehydration. Acetylated histones
accumulated in peripheral blood mononuclear cells after therapy.
Six of 73 patients had partial responses (PR), including one 17-month
complete response (CR) in a patient with diffuse large B-cell lymphoma (DLBCL).
Advanced CTCL, a disease of malignant T-cell aggregates in
cutaneous plaques and lymph nodes, is generally treated with the
retinoid bexarotene, with the immunotoxin denileukin diftitox, or
with systemic cytotoxics. Two phase II trials led to US Food and Drug
Administration approval of vorinostat in CTCL.9 A multicenter phase
IIB trial enrolled 74 patients with progressive, persistent, or recurrent
CTCL, who had received at least two prior therapies, including bexarotene.92 The patients received vorinostat 400 mg orally daily as a
single agent. The overall response rate (ORR) was 29.7%, with median
duration of response of 6.1 months and median time to progression of
9.8 months (among stage IIB and higher responders). A phase II trial
with a similar patient population found comparable results.93 In 13
patients who received 400 mg/d, the ORR was 31%, while 24.2%
responded among the entire study population of 33 patients who
received varying doses of vorinostat. The median duration of response
and time to progression were 15.1 and 30.2 weeks, respectively. Considering all patients in both phase II studies treated with 400 mg/d of
vorinostat, the most common adverse events were diarrhea, fatigue,
and nausea. Thrombocytopenia occurred in 26%, anemia in 14%.
Grade 3 to 4 adverse events occurred in fewer than 5% of patients, and
included thrombocytopenia, pulmonary embolism, fatigue, and nausea.
Notably, no serious cardiovascular events were observed. The larger
multicenter trial was recently updated in abstract form. Six of 74
patients remained on vorinostat for 2 years or longer with continued clinical effect (one CR, four PR, one stable disease), and
minimal toxicity.103
OTHER VORINOSTAT TRIALS
In the limited number of trials reported, vorinostat has modest activity
against solid tumors. A phase II study enrolled 27 women with
Table 3. Selected Clinical Trials of HDAC Inhibitors in Cancer
Study/Population
Outcome
Vorinostat90
HDAC Inhibitor
Phase I, AML or advanced hematologic malignancy, n ⫽ 41
2 CR, 2 CR with incomplete count recovery, 3 hematologic
responses
Vorinostat (with carboplatin
and paclitaxel)91
Vorinostat92
Phase I, advanced solid tumors, n ⫽ 25
Phase IIb, CTCL, n ⫽ 74
Vorinostat93
Vorinostat94
Vorinostat95
Depsipeptide96,97
Depsipeptide98
Depsipeptide99
MGCD010372
MGCD0103100
MGCD0103101
Phase
Phase
Phase
Phase
Phase
Phase
Phase
Phase
Phase
11 PR (10 NSCLC, 1 head and neck); 7 SD
1 CR, 21 PR; ORR, 29.7%; DOR, 6.1 months; TTP, 9.8
months
8 PR; ORR, 24.2%; DOR, 15.1 weeks; TTP, 30.2 weeks
1 CR, 1 SD
4 CR, 2 PR, 4 SD
3 CR, 2 PR (of 27 CTCL or PTCL); 3 CR, 8 PR (of 36 PTCL)
1 PR, 6 SD; 7% PSA response rate
1 CR, 1 PR
3 CR
2 CR, 6 PR; ORR, 38%
1 CR, 3 PR; ORR, 24%
II, CTCL, n ⫽ 33
II, relapsed DLBCL, n ⫽ 18
II, relapsed indolent NHL, n ⫽ 17
I/II, CTCL or PTCL, n ⫽ 53
II, hormone refractory prostate cancer, n ⫽ 31
II, metastatic renal cell cancer, n ⫽ 29
I, AML or myelodysplastic syndrome, n ⫽ 29
II, relapsed/refractory Hodgkin’s lymphoma, n ⫽ 21
II, relapsed/refractory DLBCL, n ⫽ 17
Abbreviations: HDAC, histone deacetylase; CR, complete response; PR, partial response; NSCLC, non–small-cell lung cancer; ORR, overall response rate; CTCL,
cutaneous T-cell lymphoma; PTCL, peripheral T-cell lymphoma; n, number of patients in trial; SD, stable disease; DOR, duration of response; TTP, time to
progression; DLBCL, diffuse large B-cell lymphoma; NHL, non-Hodgkin’s lymphoma; AML, acute myeloid leukemia.
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platinum-resistant epithelial ovarian cancer or primary peritoneal
carcinoma for treatment with vorinostat 400 mg/d. Two women
were progression free at 6 months, and one had a PR.104 A small
phase II trial of single-agent vorinostat in metastatic head and neck
cancer yielded no confirmed PRs or CRs.105 An encouraging phase
I study added vorinostat on a dose escalation schedule to carboplatin and paclitaxel in advanced solid malignancies.91 Eleven of 25
patients (10 of 19 patients with NSCLC and one of four with head
and neck cancer) achieved a PR. Vorinostat metabolism was delayed when combined with paclitaxel/carboplatin, but paclitaxel
pharmacokinetics were unaffected. These data have led to an ongoing phase II National Cancer Institute–sponsored trial of vorinostat with paclitaxel/carboplatin in NSCLC. Early results of other
phase II studies of single agent vorinostat in solid tumors have been
presented, with isolated responses in NSCLC,106 glioblastoma
multiforme,107 and breast cancer.108,109
HDAC inhibitors are also showing clinical promise in B-cell
lymphomas; vorinostat trials have only been published in abstract
format thus far. A phase II study of oral vorinostat in relapsed DLBCL
showed a CR in one of 18 patients for more than 468 days and stable
disease in one patient for 301 days.94 A second phase II trial was
performed in 17 patients with relapsed indolent non-Hodgkin’s lymphoma treated with vorinostat 200 mg twice daily for 14 days of a
21-day cycle. Four patients achieved a CR, two had PRs, and four
patients had stable disease.95
Phase I data also demonstrated activity of oral vorinostat as single
agent therapy in AML. A dose escalation study using oral vorinostat in
41 total patients enrolled 31 with AML, three with MDS, four with
chronic lymphocytic leukemia, two with acute lymphoblastic leukemia, and one with chronic myeloid leukemia. The MTD on two
different dosing schedules was 200 mg twice daily or 250 mg three
times daily, each given for 14 days of a 21-day cycle. DLTs were fatigue,
nausea, vomiting, and diarrhea. Seven patients with AML had hematologic responses, including two CRs and two CRs with incomplete
count recovery.90
DEPSIPEPTIDE
The cyclic tetrapeptide depsipeptide had clinical efficacy when given
by intravenous infusion in a case series of four patients with CTCL or
peripheral T-cell lymphoma (PTCL). Three patients with CTCL had a
PR, and one patient with PTCL achieved a CR after 6 months of
therapy.96 In a parallel phase I study that did not include those four
patients, depsipeptide had a favorable safety profile, and the MTD was
17.8 mg/m2 given on days 1 and 5 of a 21-day cycle. The DLTs
included fatigue, nausea, vomiting, thrombocytopenia, and atrial fibrillation.71 The same authors have presented interim data of a phase
II trial of depsipeptide in CTCL or PTCL, with an ORR of 37% (three
CRs and seven PRs in 27 patients).97 Several phase I trials have found
little to no clinical benefit of single-agent depsipeptide in refractory
neoplasms including AML/MDS, CLL, lung cancer, and renal cell
cancer.99,110-113 A phase II trial of single-agent depsipeptide in 31
patients with hormone refractory prostate cancer showed a shortterm disease control rate of 14% (radiographic PR or disease stabilization) and a prostate-specific antigen response rate of 7%.98 Despite
modest clinical efficacy, the drug was relatively well tolerated and
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thus these data suggest that combination clinical trials of depsipeptide with cytotoxic chemotherapy, or with other targeted agents,
may be warranted.
MGCD0103
The benzamide MGCD0103 is an orally bioavailable HDAC inhibitor
with activity in hematologic malignancies, including myeloid leukemia and lymphoma. Phase I data demonstrated a favorable safety
profile and showed activity as a single agent leading to a bone marrow
CR in three of 29 patients with AML. The MTD was 60 mg/m2
administered orally three times weekly, with DLTs of fatigue, nausea,
vomiting, and diarrhea.72 In interim analysis of an ongoing phase II
trial of MGCD0103 in relapsed or refractory Hodgkin’s lymphoma,
38% of patients responded, with median time to response of 8 weeks.
Six of 21 patients had a PR, and two had a CR with ongoing
progression-free survival of 270 and 420 days respectively, at time of
reporting.100 Similar encouraging results were seen with MGCD0103
in a phase II trial in relapsed or refractory DLBCL, where a response
rate of 24% was reported in a small cohort. Of 17 patients, one CR and
three PRs were achieved, with duration of response ranging from 112
to 336 days.101
OTHER INHIBITORS
Several other HDAC inhibitors have shown promise in early phase I or
small phase II trials. The hydroxamate panobinostat (LBH589)114,115
and the benzamide entinostat (SNDX-275)116-119 both have attractive
preclinical and phase I safety and efficacy profiles, with evidence of
activity in CTCL and AML. Like vorinostat, panobinostat and entinostat are active against transformed cells in culture, and trials are
ongoing in relapsed and refractory lymphoid malignancies, myeloid
leukemia, and solid tumors.
Early clinical data suggest utility of valproic acid as an HDAC
inhibitor, in combination with hypomethylating agents 5-azacitidine
or 5-aza-2⬘-deoxycytidine, or with the differentiating agent retinoic
acid, in AML or advanced MDS.120,121 Although generally welltolerated, valproic acid may be eclipsed by more potent and specific
HDAC inhibitors. In addition, numerous phase I trials and preclinical
data beyond the scope of this review justify further clinical studies of
HDAC inhibitors alone or in combination with cytotoxic or targeted
drugs in cancer (a more comprehensive list of clinical trials data has
been recently reviewed74).
TOXICITY
In phase I and II trials, the safety profile of HDAC inhibitors has been
favorable,especiallyincomparisontotraditionalcytotoxicchemotherapy. Combination therapy with chemotherapeutic drugs has not required substantial dose modification of either the HDAC inhibitor or
the cytotoxic drug(s). The most frequent toxicities, common to most
HDAC inhibitors tested, are fatigue, nausea, and diarrhea. Myelosuppression is relatively mild, with thrombocytopenia predominating
over anemia or neutropenia.9
The most worrisome adverse effect has been cardiac toxicity,
including ventricular arrhythmia. This toxicity may be a class effect of
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Histone Deacetylase Inhibitors in Cancer Therapy
the HDAC inhibitors, and has been proposed to occur through interaction with the HERG K⫹ channel.122,123 A phase II study of depsipeptide in 15 patients with metastatic neuroendocrine tumors was halted
early after several cardiac events occurred. One patient may have died
from a fatal ventricular arrhythmia, while two had asymptomatic
nonsustained ventricular tachycardia and three developed a prolonged QTc interval.124 A systematic study of cardiac function was
performed in a subset of patients enrolled in a phase II trial of depsipeptide in CTCL. Transient ECG changes (T wave flattening, ST
segment depression) occurred in more than half of patients after
intravenous infusion, and almost all patients had a small increase in
the QTc interval (median increase 14 milliseconds).125 Phase II and III
studies of this agent have proceeded without interruption after this
regulatory review.
Serious cardiac toxicity has not been reported with vorinostat.
In a phase II trial in CTCL, 15 of 74 patients had grade 1 to 2
electrocardiographic changes, including three with QTc prolongation.92 The hydroxamate LBH589 and its structural predecessor
LAQ824 both prolong the QTc interval.126,127 Although one patient on intravenous LAQ824 developed 10 seconds of torsades de
pointes, most patients had asymptomatic prolongation of the QTc
by fewer than 20 milliseconds. Studies of both depsipeptide and
LAQ824 revealed no long-term changes in echocardiographic parameters.125,127 However, because of toxicity concerns, patients
with significant heart disease, baseline prolonged QTc interval, or
those who need medications which prolong the QTc, have been
excluded from HDAC inhibitor trials. Cardiac toxicity may be
associated with inhibitor potency, as there is less QTc prolongation
with vorinostat than the more potent hydroxymate LBH589. Phase
I trials with entinostat have not revealed significant evidence of
QTc prolongation, suggesting that separation of efficacy and cardiac toxicity may be possible.116,117,119
BIOMARKERS
Molecular analysis of tumor samples would ideally discriminate which
patients would benefit from HDAC inhibitor therapy. Knockdown of
HDAC1, but not HDAC2 or HDAC3, conferred partial resistance to
belinostat-induced cell death in a human cervical cancer cell line.128
Although these data are provocative and suggest that high HDAC1
levels may be associated with sensitivity to inhibitor treatment, further
study will be needed to determine if a tumor-specific HDAC isoenzyme profile predicts response to individual HDAC inhibitors. NonHDAC gene expression patterns may also predict response to
treatment. Molecular profiling of NSCLC cell lines treated with trichostatin A or vorinostat showed that a nine gene RNA expression
signature predicted sensitivity to HDAC inhibitor-induced apoptosis.129 A retrospective analysis of pretreatment CTCL skin biopsies
found that high nuclear STAT1 and phospho-STAT3 staining in lymphoma cells correlated with lack of clinical response to vorinostat.130
Clinical studies have not yet used such biomarkers to select patients, or
to predict response to HDAC inhibitor treatment.
SUMMARY
HDAC inhibitors have shown promise in therapy for human lymphoid cancers in early clinical trials. Vorinostat is approved for the
www.jco.org
treatment of relapsed or refractory CTCL, and other HDAC inhibitors, particularly depsipeptide, appear to have clinical benefit in
this disease, while MGCD0103 produced multiple responses in
lymphoma and AML. In general, HDAC inhibitors are well tolerated with minimal adverse effects, although cardiotoxicity, particularly arrhythmia, may be a class toxicity that needs to be evaluated
further in larger populations of treated patients and warrants caution in using HDAC inhibitors in patients with underlying
heart disease.
An important consideration moving forward is the significant
diversity in the cellular pathways affected by HDACs. In addition to
deacetylation of histones, these enzymes affect the acetylation status of
many other nuclear and cytoplasmic proteins, including the important chaperone HSP90. Inhibitors of HDACs appear to have global
effects. HDAC inhibition may thus not be a targeted therapy in comparison to kinase inhibitors or monoclonal antibodies, as it has
broader, and at this point incompletely understood, effects on a wide
array of cellular proteins.
There are several HDAC inhibitor drugs available or in clinical
development, differing in potency and enzyme specificity. Given
the protean actions of HDACs and the differences in the effects of
individual HDAC inhibitors, it may be incorrect to make generalizations based on results with specific drugs in laboratory testing or
clinical trials. Several important questions remain. Which HDAC
enzymes are most critical in maintaining a neoplastic phenotype?
Will the most effective drugs narrowly target one class or a single
HDAC, or will the less specific HDAC inhibitors succeed by influencing multiple cellular pathways simultaneously? Are the adverse
effects, particularly cardiac, linked to inhibition of only certain
HDAC enzymes, and could more isoenzyme-specific inhibitors
have an improved therapeutic window? Preclinical investigation by
targeted knockdown of individual HDAC isoenzymes, or by development of more isoenzyme-specific inhibitors for clinical use, may
be required to elucidate these subtle biologic differences.
Despite the yet unanswered biologic questions, and while
these drugs may not act as directly targeted therapies, they appear
to alter the balance of a tumor cell such that it is more prone to
differentiation, growth arrest, and apoptosis. Given the early success of HDAC inhibitors in several cancers, we anticipate further
benefits of this new class of drugs, both as single agents and in
combination therapy.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Andrew A. Lane, Bruce A. Chabner
Administrative support: Andrew A. Lane, Bruce A. Chabner
Collection and assembly of data: Andrew A. Lane
Data analysis and interpretation: Andrew A. Lane
Manuscript writing: Andrew A. Lane, Bruce A. Chabner
Final approval of manuscript: Bruce A. Chabner
© 2009 by American Society of Clinical Oncology
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5465
Lane and Chabner
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